甲状腺功能障碍与腔隙性卒中的因果关系：一项双向、两样本孟德尔随机化研究

Causality between thyroid dysfunction and lacunar stroke： a bidirectional，two-sample Mendelian randomization study

摘要:

目的 通过两样本孟德尔随机分析（Mendelian randomization，MR）探讨甲状腺功能障碍与腔隙性卒中之间的因果关系。方法 从已发表的全基因组关联研究（genome-wide association studies，GWAS）中提取甲状腺功能减退症、甲状腺功能亢进和腔隙性卒中的GWAS汇总数据，分别包含494 577、172 938和254 459个样本。在正向MR分析中，本研究以甲状腺功能减退和甲状腺功能亢进作为暴露，分别获取了103和5个单核苷酸多态性（single nucleotide polymorphism，SNP）作为工具变量（instrumental variable，IV），以腔隙性卒中作为结局。在反向MR分析中，以腔隙性卒中作为暴露获取了3个SNP作为IV，以甲状腺功能减退和甲状腺功能亢进作为结局。双向MR分析均应用逆方差加权（inverse variance weighted，IVW）作为主要分析方法，加权中位数（weighted median，WM）和MR-Egger作为补充分析方法以评估因果效应。同时还进行了异质性和多效性检验并使用留一法分析评估结果的稳定性。结果 遗传预测的甲状腺功能减退与腔隙性卒中的风险增加相关（IVW：OR=1.118，95%CI=1.030~1.214），未发现甲状腺功能亢进对腔隙性卒中（IVW：OR=1.011，95%CI=0.958~1.067）以及腔隙性卒中对甲状腺功能减退（IVW：OR=1.093，95%CI=0.996~1.200）和腔隙性卒中对甲状腺功能亢进（IVW：OR=0.857，95%CI=0.556~1.320）存在因果关联。结论 甲状腺功能减退与腔隙性卒中风险增加有关，在甲状腺功能亢进对腔隙性卒中的研究及反向研究中并未发现因果关联，该研究结果需要进一步的实验室研究进行验证，以及未来更大样本量的研究提供证据支持。

Abstract:

Objective To explore the causality between thyroid dysfunction and lacunar stroke using two-sample Mendelian randomization（MR） analysis.Methods The study extracted summary data from published genome-wide association studies（GWAS） for hypothyroidism，hyperthyroidism，and lacunar stroke，comprising 494 577，172 938，and 254 459 samples，respectively. In the forward MR analysis，hypothyroidism and hyperthyroidism were used as the exposure，with 103 and 5 single nucleotide polymorphisms（SNPs） selected as instrumental variables（IVs），respectively，and lacunar stroke as the outcome. In the reverse MR analysis，lacunar stroke was used as the exposure，with 3 SNPs selected as IVs，and hypothyroidism and hyperthyroidism as the outcomes. Bidirectional MR analyses were performed using the inverse variance weighted（IVW） method as the primary analysis method，and weighted median（WM） and MR-Egger methods were used as supplementary analysis methods to evaluate causal effects. Additionally，heterogeneity and pleiotropy tests were conducted，and the leave-one-out analysis was employed to assess the stability of the results.Results Genetic predisposition to hypothyroidism was significantly associated with an increased risk of lacunar stroke（IVW：odds ratio［OR］=1.118，95%CI=1.030-1.214）. No causal association was found between hyperthyroidism and lacunar stroke（IVW：OR=1.011，95%CI=0.958-1.067），lacunar stroke and hypothyroidism（IVW：OR=1.093，95%CI=0.996-1.200），and lacunar stroke and hyperthyroidism（IVW：OR=0.857，95%CI=0.556-1.320）.Conclusion Hypothyroidism is causally related to an increased risk of lacunar stroke. However，no causal associations were found for hyperthyroidism and lacunar stroke or in the reverse study. These results require further verification through laboratory investigation and evidence from future studies with larger sample sizes.